This invention relates to the general area of drug-delivery systems that are based on resorbable matrices. Sustained and/or controlled release of medicinal agents and other bioactive substances are the primary uses of these systems.
Polymer matrices designed for controlled release of bioactive compounds can be non-resorbable or resorbable. In general, resorbable means degradable in the body by erosion from the surface or breakdown from within. The mechanism can involve either a chemical reaction, such as hydrolysis, or dissolution.
Non-resorbable polymers, such as polymethylmethacrylate, have been used for antibiotic delivery. These materials suffer from the disadvantage that they must be retrieved, which involves a second intervention and entails the risk of infection (HW Bucholz, et al., (1970) Chiburg, 43, 446).
Resorbable polymer matrices for controlled release are usually based on an oxygenated monomer, which is condensed in organic solvent to yield the polymeric product. The bioactive agent and the polymer are then combined in such a way as to give a timed-release formulation. The combination of active ingredient and polymer often involves organic solvents as well. The use of organic solvents is a decided disadvantage, especially when large-scale production is required. Toxic residues of organic solvents are a concern. Proteins and many polypeptides are incompatible with organic solvents.
The types of polymers in this category include:
polyesters
polyanhydrides
polyketals
poly(orthoesters)
polyurethanes
(Burkersroda, F V and Goepferich, A M in Biomedical Materials, T Neenan, M Marcolongo and R F Valentini, eds. (1999), page 23, Materials Research Society, Warrendale Pa.).
Naturally occurring proteins may be used as structural components in drug-delivery matrices (Royer, U.S. Pat. No. 4,349,530; Royer, U.S. Pat. No. 5,783,214; Lee, Science (1981) 233-235). One deficiency of proteinaceous delivery matrices is that they can exhibit instability especially in environments where an inflammatory reaction is present such as a site of localized sepsis.
WO 99/15150 discloses a stable, yet practical composition for use in inflamed sites comprising an inorganic compound, a matrix polymer and/or a complexing agent. This composition has the advantage of being biocompatible but, unlike synthetic organic polymers, no non-aqueous solvents are required in the preparation. The drug is incorporated as a solid or as part of the matrix polymer solution. The material can also be used as a cement, that is, it can be injected directly into a lesion and allowed to solidify in situ.
It is an object of this invention to provide a safe resorbable delivery system that can be designed and fashioned to provide controlled release of bioactive substances over a pre-determined time-course.
It is an object of this invention to provide a delivery matrix which when installed as an injectable liquid can solidify in the presence of moisture.
It is an object of this invention to provide a delivery matrix with enhanced stability in acidic and neutral media.
It is an object of the present invention to provide a delivery matrix with improved molecular complexing agents.
The subject invention relates to a delivery matrix formed by mixing:
a. an inorganic compound capable of undergoing hydration and/or crystallization, plus,
b. a conditioning agent which improves stability, extends the residence time, and provides for control of the release profile, and optionally,
c. a matrix polymer, and/or
d. a complexing agent.
Mixing a bioactive agent with the above components results in a solid composition that is capable of providing sustained release of said agent over a predetermined time period.
A. Introduction
The inorganic compound-conditioning agent composites described herein are resorbable by dissolution. No acid is produced as opposed to hydrolytic erosion of polymer matrices such as polyesters.
The inorganic-conditioning agent composite described herein requires no organic solvent in matrix preparation or drug loading. No acid is produced on erosion so it is useful for orthopedic applications. The inclusion of the conditioning agent and advantageously the matrix polymer imparts control over the release profile of the active ingredient and distinguishes this material from unadulterated plaster of Paris which is rigid and safe but is otherwise lacking in performance (D Mackey, et al. (1982) Clin. Orthop. 167, 263; G W Bowler, et. al. (1994) J. Trauma, 36, 331). The matrix described in commonly-owned WO 99/15150 may also contain a complexing agent to retard the release of the active ingredient.
The matrix formulation of this invention contains improved hydrophobic complexing agents, e.g., pamoates, and conditioning agents which can serve as water repellants. Water repulsion of these matrices allows for set-up in an aqueous environment. In fact, when a conditioning agent is present, the matrix will solidify when totally submerged. This trait is important when the material is used in orthopedic or dental applications. Examples include filling of periodontal defects or treating an osteomyelitic lesion. Also, the lifetime in the environment, or the body, is extended. This extended residence time is important in the delivery profile. Multiple formulations with different residence times can be combined. The resultant release profile has a desirable form and resembles zero-order. When hydrophobic complexing agents and conditioning agents are used with hydrophobic medicinal agents, the release profiles can be controlled.
Entrapment of bioactive substances within the resorbable biocompatible matrix described herein yields a delivery system, which permits controlled and localized release of a bioactive agent. Inorganic compounds such as CaSO4xe2x80x941/2 H2O (calcium sulfate hemihydrate) can be combined with a polymer in the presence of a bioactive agent to produce a solid which constitutes a biocompatible and resorbable delivery matrix (See WO 99/15150xe2x80x94the entire contents of which is incorporated by reference herein). The matrix polymer increases the internal viscosity of the device, which slows the efflux of the bioactive agent.
The production of and advantageous embodiment of the delivery system can be illustrated as follows: 
When contacted with water, calcium sulfate hemihydrate is converted to the dihydrate, CaSO4xe2x80x942 H2O, which crystallizes. The mass of needle-like crystals produces a porous matrix with high compressive strength, as much as 2000 psi or more. A conditioning agent such as calcium stearate is pre-mixed with the calcium sulfate hemihydrate. The slurry can be injected into the desired location with solidification in situ. This composition is ideal for dental and orthopedic applications. The fact that the slurry can set-up in the presence of moisture is very advantageous.
The delivery matrix is formed by mixing:
a. an inorganic compound capable of undergoing hydration and/or crystallization, plus
b. a conditioning agent, and optionally
c. a matrix polymer, and/or
d. a complexing agent.
The nature and amount of matrix polymer, the relative proportions of calcium sulfate hemihydrate and liquid, the complexing agent, and the nature and amount of the conditioning agent permit the adjustment of the release profile and residence time of the matrix.
The use of a conditioning agent such as calcium stearate provides improved stability and added control of the release profile and residence time. In addition, it imparts the desirable feature of moisture resistance, which preserves the shape of the mass while setting. When the composition containing calcium stearate is fully submerged after thorough blending, the mass remains intact and setting occurs. This attribute is very important as it allows the installation of the composition into moist areas such as a tooth socket or bone lesion. Water repulsion can also stabilize the solid dosage form with extension of residence time. Calcium stearate is included at a rate of up to 30% w/w, advantageously 2.5-20% ww, based on the amount of inorganic compound, e.g., calcium sulfate hemihydrate. Even higher levels of calcium stearate are obtainable depending on the nature and amounts of other components.
B. Production of Dosage Forms
A delivery matrix of the invention is produced by:
a. blending of an inorganic such as calcium sulfate hemihydrate and a conditioning agent such as calcium stearate, both in powder form,
b. mixing with matrix polymer solution (the drug may be dissolved or suspended in the polymer solution),
c. solidification in a mold or in bulk, and
d. unmolding or preparing of microbeads by milling and sizing.
The molds made of stainless steel or teflon can be used to prepare cylinders or spheres (e.g., both 3 mm in diameter). The preparation of wafers is also possible. Microbeads can in turn be compressed into tablets with various binding agents to yield another dosage form.
A representative formulation follows:
When the amount of calcium sulfate hemihydrate is set at about I g, the amount of bioactive substance is set in the range of 1-300 mg. The concentration of polymer can be up to 50% (w/v). The conditioning agent is present in the range of 5-30% (w/w) based on calcium sulfate. The ratio of liquid/solid is preferably 0.6.
The calcium sulfate hemihydrate can be sterilized by dry heat (140xc2x0 for 4 hr); the polymer solution is sterilizable by filtration (0.2-micron filter). Terminal sterilization by gamma irradiation at 15-18 kGy is also effective.
A compilation of useful formulations is shown below in Table 1.
1. Inorganic Compounds
Calcium sulfatexc3x971/2H2O (hemihydrate) (hh) is the preferred inorganic component. The hemihydrate takes up water and crystallizes as the higher hydrate. Unadulterated calcium sulfate matrix exhibits poor drug release profiles. With conditioning agents, and optionally matrix polymers and complexing agent-active agent complexes the release profiles are improved. Other inorganics can be employed such as calcium silicates, aluminates, hydroxides and/or phosphates (see pages 72, 95, 327 in Reference Book of Inorganic Chemistry (1951) Latimer, W. H., and Hildebrand, J. M., Macmillan, New York, hereby incorporated by reference in its entirety).
2. Conditioning Agents
Conditioning agents are used to slow the erosion rate and permit solidification in the presence of moisture (repels water). All conditioning agents have a hydrophobic moiety. Calcium stearate is an advantageous choice for a conditioning agent that meets the criteria of safety and efficacy. Other calcium salts are useful in this regard. Examples include saturated and unsaturated carboxylic acids, aromatic carboxylic acids, corresponding phosphates, phosphonates, sulfates, sulfonates, and other compounds containing a hydrophobic moiety with a negatively charged anion. Salts of undecylenic acid are useful, in that they provide stability and also antifungal action. The use of calcium as the cation is advantageous but other cations will suffice; the group includes, but is not limited to, zinc, magnesium, aluminum and manganese. The generalized chemical structure can be illustrated as follows:
Rxe2x80x94Xxe2x80x94M
where R is alkyl, alkenyl, alkynyl or aryl,
where X is a carboxylate, a carboxylic acid, an aromatic carboxylic acid, a corresponding phosphate, a phosphonate, a sulfate, or a sulfonate, and
where M is a metal ion such as calcium, zinc, magnesium, aluminum or manganese.
An example is calcium stearate, (CH3[CH2]16COO31 )2Ca2+
In this case Rxe2x95x90CH3[CH2]16, Xxe2x95x90COOxe2x88x92, and M is the metal ion Ca+.
Cationic conditioning agents can also be employed, i.e.,
Rxe2x80x94Pxe2x80x94Y
where R=alky, alkenyl, alkynl or aryl,
where P=ammonium, or alkyl ammonium, and
where Y=sulfate or phosphate.
3. Matrix Polymers
The preferred matrix polymers for medical use are
biocompatible (non-toxic, non-allergenic, non-immunogenic)
water soluble
compatible with other components in the formulation
Examples of matrix polymers include chondroitin sulfate, dextran (1-50%) hyaluronic acid (e.g., 1-5%), dextran sulfate, pentosan polysulfate, polyethylene glycol, polyvinylpyrrolidone, proteins such as collagen (gelatin) and fibrinogen and polypeptides. In an advantageous embodiment, a crosslinking agent is added to the matrix polymer. The addition of the crosslinking agent causes a reaction which leads to a higher molecular weight matrix polymer which increases viscosity Diffiusion is thereby inhibited. See Royer U.S. Pat. No. 5,783,214 hereby incorporated by reference in its entirety. Counterions, are advantageously sodium or calcium. Chitosan as well as cationic polypeptides, polylysine, and polyarginine are examples of useful polymers that are positively charged at neutral pH.
The function of the matrix polymer is to control the viscosity, which is dependent on the nature, molecular weight and concentration of the polymer. The rationale for using polymers and polymeric complexing agents is based on Stokes law:
Dxe2x88x9d1/Mv
D=the diffusion coefficient
M=the molecular weight of the medicinal
v=the viscosity of the medium
4. Complexing Agents
To the extent that polymeric complexing agents increase the effective molecular weight of the active ingredient, the rate of efflux is slowed according to D xe2x88x9d1/Mv. Complexing agents can be polymers or small molecules. The agents can form ionic bridges or hydrophobic bonds with the molecule to be delivered. The complexes involving the bioactive agents can range from sparingly soluble to soluble. Disodium pamoate is a good example of a complexing agent that forms sparingly soluble adducts with cationic bioactive ingredients. Disodium methylene disalicylate is a similar molecule to disodium pamoate that performs the same function. Procaine and benzathin can be used to reduce the solubility and rate of efflux of anionic bioactive agents. Additional complexing agents are presented in WO 99/15150.
C. Uses of the Compositions of the Invention
Medicinals (both non-protein drugs and medicinal proteins) useful with the matrices of the invention are presented in WO 99/15150. Therapeutics, antigens, adjuvants, and regulatory molecules such as hormones exemplify bioactive agents with medical applications.
The matrix prepared as described above can be combined with soluble bioactive agent and optionally a complexed bioactive agent, to provide an initial burst and intermediate control. As an example clindamycin-HCl free in solution, plus clindamycin-pamoate (as a sparingly soluble salt complex), plus clindamycin-pamoate encapsulated as above in the calcium sulfate-conditioning agent-polymer matrix comprise a three component system for delivery of clindamycin with a desirable release profile. This combination has been employed to provide an antibiotic depot in cats and dogs. Alternatively, a depot can be formed of the soluble drug and the complexed drug alone.
Another embodiment of the invention is a formulation containing a mixture of Drug calcium sulfate, Drug calcium sulfate-calcium stearate 2.5%, Drug calcium sulfate-calcium stearate 5.0% and Drug calcium sulfate-calcium stearate 10%.
Antibiotic formulations can be used to treat localized infections such as osteomyelitis, joint infections, and diabetic foot ulcers. Subsequent to surgical debridement (drainage), beads (e.g., 3 mm), microbeads, or cement is installed at the site of the infection. Infected screw channels in bones can be treated successfully using amikacin cement. Microbeads containing amikacin pamoate are effective in the treatment of joint sepsis. For dead space management following surgical repair of fractures, antibiotic cement can be used.
Another use of antibiotic matrix involves dentistry. Periapical abscesses can be treated with microbeads containing amikacin/clindamycin. Doxycycline cement can be administered by syringe to fill periodontal defects (See Example 16).
Antiparasitics such as ivermectin can be delivered using the delivery system of the invention.
Various anti-infectives useful in conjunction with the formulations of the invention include gentamicin, clarithromycin, doxycycline minocycline and lincomycin, amikacin, penicillin, cefazolin, ciprofloxacin, enrofloxacin, norfloxacin, silver sulfadiazine, imipenem, piperacillin, nafcillin, cephalexin, cefoperazone, vancomycin, tobramycin, nystatin, and amphotericin B or salts thereof (e.g., pamoate salt). Forming the pamoate (a complexing agent) of these anti-infectives to form complexes such as amikacin pamoate, clindamycin and gentamicin pamoate, are useful alone or in the formulations of the invention.
Cis-platin, and other anti-neoplastic agents, can be delivered locally with beads (e.g., 3 mm) or with microbeads prepared as described herein. In one embodiment, localized administration is beneficial in that systemic toxicity is eliminated but concentrations in the area of cancerous tissue are high.
Vaccine antigens can be delivered with the system of the invention, for example, with microbeads (i.m. injection). With only a single injection, a contraceptive antigen (hCG/Dt) elicited long-lived antigenicity (36 weeks) which is sufficiently high to prevent pregnancy. The system of the invention can also be used to deliver DNA and RNA antigens.
The delivery system of the invention can also be used to deliver non-medical bioactive agents include sterilants, pheromones, herbicides, pesticides, insecticides, fungicides, algicides, growth regulators, antiparasitics, repellents, and nutrients. (See also WO 99/15150).
D. Production of the Matrix and Modes of Administration
Administration of the solid matrix can be by surgical implant, oral, i.p., i.a. or p.a. The liquid injection can be s.c., i.m, or i.p. Advantageously, the administration is done by parenteral injection.
a. Cement
1 g of calcium sulfate/calcium stearate (1-25% w/w) plus amikacin pamoate (100-320 mg) are thoroughly mixed and contacted with 0.6 ml of aqueous dextran sulfate (10% w/v). After blending to a smooth slurry (30s), the material is transferred to a 5 ml syringe and installed in vivo where it solidifies. Amikacin sulfate can be blended with amikacin pamoate to adjust the release profile. Presence of the calcium stearate allows for the solidification in the presence of moisture.
b. Beads/Cylinders
Sterile 3 mm beads can be installed individually with mosquito forceps or in groups using a cannula. A teat cannula is a safe tool for installation of beads and cylinders. This approach has been successfully used in the treatment of squamous cell carcinoma via intralesional chemotherapy with 3 mm beads of the invention containing cis-Pt (7%).
c. Microbeads
Injection
Sterile microbeads (45-150 microns) (dry) are suspended in a suitable liquid for injection just prior to use. When antibiotics are involved, a solution of the antibiotic of choice may be used as the suspending liquid. For example, in treating a septic joint, amikacin solution (3 mil/25%) is used to suspend microbeads (300 mg) containing amikacin pamoate prepared as described in Example 4. An xe2x80x9cinitial burstxe2x80x9d provided by the soluble amikacin sulfate is followed by the amikacin that elutes from the microbeads. A similar approach is appropriate for creating a subcutaneous depot of antibiotics and other active ingredients.
Oral
Microbeads are mixed with food or feed. The composition of the invention is tasteless and in some cases will mask the taste of a bioactive compound. In addition, the microbeads of the invention can be included in a capsule for oral delivery.